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Journal of Neuroscience, Vol 12, 3466-3472, Copyright © 1992 by Society for Neuroscience
Pharmacological characterization of GABAB-mediated responses in the CA1 region of the rat hippocampal slice
JM Solis and RA Nicoll
Department of Pharmacology, University of California, San Francisco 94143-0450.
It is generally accepted that the bicuculline-resistant responses to GABA
are mediated through the activation of GABAB receptors that mediate a slow
IPSP. However, a number of reported observations are difficult to reconcile
with this model. Specifically, GABAB antagonists only partially block
bicuculline-resistant GABA responses, and both 4- aminopyridine (4-AP) and
carbachol have been reported to block responses to the selective GABAB
agonist baclofen, but not GABA itself. Thus, it has been argued that
baclofen and GABA increase potassium conductance through separate receptor
mechanisms. This suggestion is not easily reconcilable with the postulated
physiological role of GABAB receptors in mediating the slow IPSP. We have
addressed these discrepancies by using the new GABAB antagonists
2-hydroxy-saclofen (2- OH-SAC) and CGP 35348 in the presence of the GABA
uptake inhibitor SKF 89976A. The weak antagonism of 2-OH-SAC against the
bicuculline- resistant GABA response was improved when the GABA uptake was
inhibited with SKF 89976A, allowing for the application of lower GABA
concentrations. Under these circumstances, 2-OH-SAC and CGP 35348 strongly
antagonized GABA and baclofen responses, but did not have any effect on
outward currents evoked by 5-HT. The slow IPSP evoked in the presence of
glutamate antagonists was reversibly inhibited by CGP 35348 (IC50 = 14
microM), without affecting the fast IPSP. Carbachol (0.3-20 microM) had no
effect on outward currents evoked by either baclofen or GABA. 4-AP (5
microM to 1 mM), despite causing a large increase in cell excitability, did
not change baclofen responses. Higher concentrations of 4-AP (5 mM) induced
inward current, and reduced both baclofen and GABA outward currents to a
similar extent.(ABSTRACT TRUNCATED AT 250 WORDS)
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